Sepsis is defined as a disease which has infectious cause and which shows the pathology of systemic inflammatory response syndrome (SIRS) (see Non-Patent Document 1). Initial symptoms found include ague, sweating, fever, and decrease in the blood pressure, and when various inflammatory mediators and blood coagulation factors increase in the whole body, disturbance in the microcirculation occurs, and this results in the worsening of the pathological conditions including tissue and organ failures, which often lead to continuous onset of multiple organ failure or septic shock resulting in the death.
Onset of the sepsis is triggered by action of the components constituting the infectious bacteria, for example, lipopolysaccharide (LPS) of Gram-negative bacteria and lipoteichoic acid (LTA) in Gram-positive bacteria with leukocyte (monocyte/macrophage and neutrophil) or vascular endothelial cell, which in turn causes production of various inflammatory mediators. Recent studies revealed that CD14 which was first found as a differentiation antigen of leukocyte (see Non-Patent Document 2) and Toll-like-receptors (TLR) which are accepted to be pattern recognition molecules in the innate immune system (see Non-Patent Document 3) play an important role in such activation of the target cell by the bacterial constituent components.
CD14 is present in two forms, namely, in membrane-bound form and soluble form. The membrane-bound form CD14 is anchored to cell membrane by glycosylphosphatidyl-inositol, and the soluble form CD14 includes the one synthesized in liver and the one present in blood after cleavage on leukocyte by phosphatidylinositol-specific phospholipase (see Non-Patent Document 4). For example, activation of the target cell by LPS is caused by binding of the LPS to the CD14 promoted by catalytic action of LPS-binding protein (LBP) in blood and the subsequent binding to the TLR on the cell membrane which results in the transduction of the activation signal to the target cell. The target cell which has received the activation signal produces and expresses various mediators related to inflammatory response, for example, cytokines such as TNF-α, IL-1, IL-6, and IL-8 and tissue factors. The cytokine which is a typical mediator activates neutrophil and macrophage, and this causes adhesion to vascular endothelium, migration in the tissue, release of neutral proteases such as neutrophil elastase, and production of reactive oxygen species. Activation of the coagulation and fibrinolytic system, activation of the complement system, and activation of kallikrein also contribute for this process. As described above, a large number of mediator molecules and effector molecules are involved at the molecular level and the cell level with the formation of the pathology, and excessive promotion of these reactions results in the systemic damage, which leads worsening of the pathology from the microcirculatory disturbance to the tissue failure and organ failure as described above.
In order to cope with the sepsis exhibiting such complicated pathology, many studies have been conducted on the therapeutic agents. The approaches employed in developing the therapeutic agents may be divided into two major categories, namely, the approach of inhibiting the action of the bacterial constituent component which is the substance responsible for the onset of the sepsis, and the approach of inhibiting various factors which are expressed as the biological response to the signal of the substance responsible for the onset of the sepsis.
The therapeutic approaches of inhibiting the action of the endotoxin from Gram-negative bacteria include (1) the method using an anti-endotoxin antibody (see Non-Patent Documents 5 and 6); (2) the method using an endotoxin antagonist (see Non-Patent Document 7); (3) a method using polymixin B (see Non-Patent Document 8); and (4) a method using BPI (see Non-Patent Document 9). Endotoxin is a component constituting Gram-negative bacteria, which is not found in the Gram-positive bacteria and fungi which are responsible for the sepsis. Accordingly, sepsis agents targeting the endotoxin are associated with the problem that they cannot cope with the bacteria and fungi other than the Gram-negative bacteria.
A sepsis agent which targets on CD14 which functions as a receptor for LPS which is a substance constituting Gram-negative bacteria has also been proposed. Since CD14 has been found to be not only the receptor for the LPS but also a receptor for a bacterial constituent such as lipoteichoic acid and peptidoglycan which are the constituents of Gram-positive bacteria (see Non-Patent Document 10), it is indicated that the sepsis agent targeting the CD14 is applicable not only to the Gram-negative sepsis. The agents that have been proposed include anti-CD14 antibodies (See Patent Documents 1 and 2) and soluble CD14 (see Non-Patent Document 11 and Patent Documents 3 and 4). These agents, however, are not yet used in practice. The pathology of sepsis has been estimated to be sequential and complex development from the stage triggering the inflammatory response with the constituent of the pathogen to a more serious stage. The drawback of the CD14 targeting agents is that, since action of these agents focuses on the early triggering stage of the pathology formation, dubiousness remains on the effects on the more serious late stage of the pathology.
In the meanwhile, of the therapeutic approaches of targeting the excessively produced factors, the therapeutic methods of inhibiting a cytokine or other inflammatory mediators include (1) the method using an anti-TNF antibody (see Non-Patent Document 12), (2) the method using a soluble TNF receptor (see Non-Patent Document 13), (3) the method using an IL-1 receptor antagonist (see Non-Patent Document 14), (4) the method using an PAF inhibitor (see Non-Patent Document 15), and (5) the method using an NO inhibitor (see Non-Patent Document 16). Although these therapeutic methods have demonstrated their effectiveness in the stage of experimental animals or in small scale clinical tests, their effectiveness and usefulness are not clearly revealed in the stage of large scale clinical test. As described above, cytokine and other inflammatory mediators each have a plurality of activities, and these mediators constitute a complicated network and various events occur in this network in which each mediator complements other mediators and induces the expression of other mediators. Therefore, it has been estimated that treatment made by inhibiting one factor has some limitation (see Non-Patent Document 17).
Also proposed is the therapeutic approach which targets blood coagulation factors whose production is enhanced in the process of the interaction of mediators associated with the generation of the pathology of the sepsis. The blood coagulation factors are believed to be included among the important targets of the therapeutic agent since enhancement of the blood coagulation invites disturbance in the blood microcirculation system, which in turn invites decrease in the amount of oxygen supplied to the peripheral tissue, tissue failure, and even multiple organ failure. Exemplary methods include (1) a therapeutic method using an activated protein C (see Non-Patent Document 18), (2) a therapeutic method using an antithrombin III (see Non-Patent Document 19), and (3) a therapeutic method using a TFPI (see Non-Patent Document 20). Among these, the treatment of severe sepsis using activated protein C has been demonstrated to have a significant therapeutic effect in a large scale clinical test (see Non-Patent Document 21), and this treatment has been offered for clinical use. However, this treatment has great clinical limitation that it is contraindicated for patients having bleeding tendency.                [Patent Document 1] JP 2744130 B        [Patent Document 2] WO 02/42333        [Patent Document 3] JP 10-512142 A        [Patent Document 4] WO 01/72993        [Non-Patent Document 1] The ACCP/SCCM Consensus Conference Committee. Chest, 1992, 101, 1644-1655.        [Non-Patent Document 2] Goyert S. M. and Ferrero E., in McMichael A. (ed.): Leukocyte Typing III. Oxford, Oxford University Press, 1987.        [Non-Patent Document 3] Zhang G. and Ghosh S., Endotoxin Res., 2000, 6, 453-457.        [Non-Patent Document 4] Stelter F., Structure/Function relationship of CD14; in Jack R. S. (ed.): CD14 in the Inflammatory Response. Chem. Immunol. Basl, Karger, 2000, 74, pp. 25-41.        [Non-Patent Document 5] Ziegler E. J., et al., New Engl. J. Med., 1991, 324, 429-436.        [Non-Patent Document 6] Greenman R. L. et al., JAMA, 1991, 266, 1097-1102.        [Non-Patent Document 7] Kawata T. et al., Prog Clin Biol Res., 1995, 392, 499-509.        [Non-Patent Document 8] Tani T. et al., Artif. Organs, 1998, 22, 1038-1045.        [Non-Patent Document 9] Lin Y. et al., Antimicrob. Agents Chemother., 1996, 40, 65-69.        [Non-Patent Document 10] Cleveland, Infect Immun., 1996, 64, 1906-1912.        [Non-Patent Document 11] Goyert S. M., J. Immunol., 1995, 154, 6529-6532.        [Non-Patent Document 12] Fischer C. J. et al., Crit. Care Med., 1993, 21, 318-327.        [Non-Patent Document 13] Fischer C. J. et al., N. Engl. J. Med., 1996, 334, 1697-1702.        [Non-Patent Document 14] Fischer C. J. et al., JAMA, 1994, 271, 1836-1843.        [Non-Patent Document 15] Dhainaut J. F. et al., Crit. Care Med., 1994, 22, 1720-1728.        [Non-Patent Document 16] Gachot B., Intensive Care Med., 1995, 21, 1027-1031.        [Non-Patent Document 17] Vincent J. L. et al., CID, 2002, 34, 1984-1093.        [Non-Patent Document 18] Rivard G. E. et al., J. Peditr., 1995, 126, 646-652.        [Non-Patent Document 19] Fourrier F. et al., Chest, 1993, 104, 882-888.        [Non-Patent Document 20] Abraham E. et al., Crit. Care Med., 2000, 28, S31-33.        [Non-Patent Document 21] Bernard, G. R. et al., N. Engl. J. Med., 2001, 344, 699-709.        